SN-38 is the active metabolite of irinotecan and acts as an effective topoisomerase I inhibitor with therapeutic effects on many malignant tumors, including some drug-resistant cancers. However, the poor solubility, low bioavailability, and severe dose-dependent toxicity limits the clinical application of SN-38. Currently, emerging macrophage membrane-coated nanoparticles provide an efficient biomimetic approach to develop novel SN-38 formulations for the reduction of its side effects. Photothermal therapy (PTT) is a promising methods in tumor treatment to thermally ablate tumors using various materials such Prussian blue nanoparticles (NPs) and can combined with chemotherapy to synergistically work. There is no report that combined SN38 and photothermal therapy for the treatment of colorectal cancer (CRC). SN38-PB@CM NPs were constructed by loading SN-38 into macrophage cell membrane-coated hollow mesoporous Prussian blue (PB) NPs. The morphology, size and zeta potential were evaluated by transmission microscopy and dynamic light scatter (DLS). Coomassie bright blue staining was performed to assess total protein profile. The photothermal properties of it were also investigated via near-infrared imaging. CCK8 and calcein-AM/PI staining were used to evaluate cell viability. Flow cytometry was performed to assess cell apoptosis. The fluorescent microscopy was used to observe cellular uptake of SN38-PB@CM NPs to assess its internalization in vitro. The biodistribution, tumor-targeting efficacy, antitumor efficacy and safety of SN38-PB@CM NPs in vivo were assessed in CT26 tumor-bearing mice via In Vivo Imaging System. SN38-PB@CM NPs were successfully constructed and exhibited a uniform size distribution (140.5 ± 4.3 nm) and an excellent drug-loading capacity (5.61 ± 0.64

Colorectal cancer (CRC) is a prevalent malignancy, ranking third in incidence among all cancers. The inherent heterogeneity and the immunosuppressive tumor microenvironment (ITME) of CRC poses significant challenges in developing effective treatment strategies. In this study, we found that etoposide (ETO) could induce immunogenic cell death (ICD) in CRC cells, highlighting its potential to activate anti-tumor immunity. To overcome the limitations of ETO's poor solubility and low bioavailability, we developed ETO-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles. Additionally, we employed biomimetic modification using CT26 cell-derived membranes to enhance tumor accumulation through homologous targeting and to evade macrophage phagocytosis. In vitro experiments confirmed the enhanced cytotoxicity and ICD characteristics in CT26 cells. In vivo studies further validated the improved tumor targeting, resulting in significant tumor inhibition. Notably, there was a marked increase in the proportion of CD8+T cells in tumors and lymph nodes (LNs), indicating an improved immunosuppressive microenvironment. The construction of ETO-PLGA@CM presents a promising approach for CRC treatment by synergistically activating specific anti-tumor immune responses.

The effect of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a persistent environmental pollutant commonly used as a flame retardant in various consumer products, on pancreatitis has not been clearly elucidated, although it has been reported to be toxic to the liver, nervous system, and reproductive system. Acute pancreatitis (AP) and chronic pancreatitis (CP) models were induced in this study by intraperitoneal injection of caerulein. The aim was to investigate the impact of BDE-47 on pancreatitis by exposing the animals to acute (1 week) or chronic (8 weeks) doses of BDE-47 (30 mg/kg in the low-concentration group and 100 mg/kg in the high-concentration group). Additionally, BDE-47 was utilized to stimulate mouse bone marrow-derived macrophages, pancreatic primary stellate cells, and acinar cells in order to investigate the impact of BDE-47 on pancreatitis. In vivo experiments conducted on mice revealed that chronic exposure to BDE-47, rather than acute exposure, exacerbated the histopathological damage of AP and CP, leading to elevated fibrosis in pancreatic tissue and increased infiltration of inflammatory cells in the pancreas. In vitro experiments showed that BDE-47 can promote the expression of the inflammatory cytokines Tnf-α and Il-6 in M1 macrophages, as well as promote acinar cell apoptosis through the activation of the PERK and JNK pathways via endoplasmic reticulum stress. The findings of this study imply chronic exposure to BDE-47 may exacerbate the progression of both AP and CP by inducing acinar cell apoptosis and dysregulating inflammatory responses.

Background: SN-38, recognized as the primary active derivative of the pivotal chemotherapeutic agent CPT-11, demonstrates substantially enhanced efficacy in colorectal cancer (CRC) management compared to CPT-11. Nonetheless, challenges such as low stability, inadequate aqueous solubility, limited bioavailability, and nonspecific targeting to cancer cells hinder its clinical adoption. In the present research, we synthesized SN-38loaded liposomes cloaked with macrophage membranes (SN-38@MM-LPs) to assess their therapeutic potential and safety profile in addressing CRC. Methods: SN-38@MM-LPs were synthesized using an incubation extrusion technique, combining a macrophage membrane with liposomes (LPs). It was characterized by size, zeta potential, transmission electron microscopy observations, polydispersity index and coomassie bright blue staining. CCK-8, EdU, and flow cytometry assays were performed to evaluate the viability and apoptosis rates of HCT116 and HCT8 cells after treatment with SN38@MM-LPs. A cellular uptake assay was conducted to evaluate the internalization of SN-38@MM-LPs in vitro. Moreover, the biodistribution, therapeutic efficacy, and safety of SN-38@MM-LPs were further assessed in orthotopic HCT116 xenograft model mice. Results: Characterization results revealed that SN-38@MM-LPs possess a spherical morphology with a consistent size distribution (129 nm) and a drug loading efficiency of 5.54 +/- 0.73%. SN-38 curtailed the growth and promoted apoptosis in both HCT8 and HCT116 cells. The impact of SN-38 was accentuated when delivered via SN-38@LPs and SN-38@MM-LPs. Notably, in the orthotopic xenograft model, SN-38@MM-LPs manifested superior tumor-targeting capabilities and therapeutic outcomes. Additionally, SN-38@MM-LPs presented negligible hepatic toxicity. Conclusions: SN-38@MM-LPs showcased potent and targeted antitumor actions in CRC. Consequently, SN38@MM-LPs emerge as a potential nanoparticle formulation that could amplify the antitumor efficacy of SN38, simultaneously mitigating liver toxicity concerns.

Acute pancreatitis (AP) is a common abdominal disease that typically resolves on its own, but the mortality rate dramatically increases when it progresses to severe acute pancreatitis (SAP). In this study, we investigated the molecular mechanism underlying the development of SAP from AP. We utilized two SAP models induced by pancreatic duct ligation and caerulein administration. Transcriptomic and proteomic analyses were subsequently performed to determine the mRNA and protein expression profiles of pancreatic samples from SAP and AP model and normal mice. To explore the role of Hspb1 in SAP, we used Hspb1 knockout (KO) mice, a genetically engineered chronic pancreatitis strain (T7D23A), Anxa2 KO mice, and acinar cell -specific Prdx1 knockout mice. Additionally, various in vivo and in vitro assays were performed to elucidate the molecular events and direct targets of Hspb1 in acinar cells. We found that Hspb1 expression was upregulated in AP samples but significantly reduced in acinar cells from SAP samples. KO or inhibition of Hspb1 worsened AP, while AAV8-Hspb1 administration mitigated the severity of SAP and reduced remote organ damage in mice. Furthermore, AAV8-Hspb1 treatment prevented the development of chronic pancreatitis. We found that KO or inhibition of Hspb1 promoted acinar cell death through apoptosis and ferroptosis but not necroptosis or autophagy by increasing reactive oxygen species (ROS) and lipid ROS levels. Mechanistically, Hspb1 directly interacted with Anxa2 to decrease its aggregation and phosphorylation, interact with the crucial antioxidant enzyme Prdx1, and maintain its antioxidative activity by decreasing Thr-90 phosphorylation. Notably, the overexpression of Hspb1 did not have a protective effect on acinar-specific Prdx1 knockout mice. In summary, our findings shed light on the role of Hspb1 in acinar cells. We showed that targeting Hspb1/Anxa2/Prdx1 could serve as a potential therapeutic strategy for SAP.

Acute pancreatitis (AP) is a common acute abdominalgia of the digestive tract. When the disease progresses to severe acute pancreatitis (SAP), the complications and mortality rate greatly increase. Determining the key factors and pathways underlying AP and SAP will help elucidate the pathological processes involved in disease progression and will be beneficial for identifying potential therapeutic targets. We conducted an integrative proteomics, phosphoproteomics and acetylation proteomics analysis of pancreas samples collected from normal, AP and SAP rat models. We identified 9582 proteins, 3130 phosphorylated modified proteins, and 1677 acetylated modified proteins across all samples. The differentiated expression proteins and KEGG pathway analysis suggested the pronounced enrichment of key pathways based on the following group comparisons: AP versus normal, SAP versus normal, and SAP versus AP. Integrative proteomics and phosphoproteomics analyses revealed 985 jointly detected proteins in the comparison of AP and normal samples, 911 proteins in the comparison of SAP and normal samples, and 910 proteins in the comparison of SAP and AP samples. Based on proteomics and acetylation proteomics analyses, we found that 984 proteins were jointly detected in the comparison of AP and normal samples, 990 proteins in SAP and normal samples, and 728 proteins in SAP and AP samples. Thus, our study offers a valuable resource to understand the proteomic and protein modification atlas in AP.

Hepatocellular carcinoma (HCC) is the tumor with the second highest mortality rate worldwide. Recent research data show that KIF11, a member of the kinesin family (KIF), plays an important role in the progression of various tumors. However, its expression and molecular mechanism in HCC remain elusive. Here, we evaluated the potential role of KIF11 in HCC. The effect of KIF11 was evaluated using the hepatocellular carcinoma cell lines, LM3 and Huh7, after genetic or pharmacological treatment. Evaluating the role of KIF11 in the xenograft animal models using its specific inhibitor. The role of KIF11 was systematically evaluated using specimens obtained from the aforementioned animal and cell models after various in vivo and in vitro experiments. The clinicopathological analysis showed that KIF11 was expressed at high levels in patients with hepatocellular carcinoma. Cell experiments in vitro showed that KIF11 deficiency significantly slowed the proliferation of liver tumor cells. And in the experiment using liver cancer cells overexpressing OCT4, overexpression of OCT4 substantially increased the proliferation of tumor cells compared with tumor cells with KIF11 knockdown alone. Both in vitro cell experiment and in vivo xenotransplantation tumor experiment showed that monastrol, an inhibitor of KIF11, could effectively delay the proliferation and migration of tumor cells. Based on these results, KIF11 is expressed at high levels in hepatocellular carcinoma and promotes tumor proliferation in an OCT4-dependent manner. KIF11 may become a therapeutic target for hepatocellular carcinoma, and its inhibitor monastrol may become a clinical antitumor drug.

Colon adenocarcinoma (COAD) is a serious public health problem, the third most common cancer and the second most deadly cancer in the world. About 9.4% of cancer-related deaths in 2020 were due to COAD. Anoikis is a specialized form of programmed cell death that plays an important role in tumor invasion and metastasis. The presence of anti-anoikis factors is associated with tumor aggressiveness and drug resistance. Various bioinformatic methods, such as differential expression analysis, and functional annotation analysis, machine learning, were used in this study. RNA-sequencing and clinical data from COAD patients were obtained from the Gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Construction of a prognostic nomogram for predicting overall survival (OS) using multivariate analysis and Lasso-Cox regression. Immunohistochemistry (IHC) was our method of validating the expression of seven genes that are linked to anoikis in COAD. We identified seven anoikis-related genes as predictors of COAD survival and prognosis, and confirmed their accuracy in predicting colon adenocarcinoma prognosis by KM survival curves and ROC curves. A seven-gene risk score consisting of NAT1, CDC25C, ATP2A3, MMP3, EEF1A2, PBK, and TIMP1 showed strong prognostic value. Meanwhile, we made a nomogram to predict the survival rate of COAD patients. The immune infiltration assay showed T cells. CD4 memory. Rest and macrophages. M0 has a higher proportion in COAD, and 11 genes related to tumor immunity are important. GDSC2-based drug susceptibility analysis showed that 6 out of 198 drugs were significant in COAD. Anoikis-related genes have potential value in predicting the prognosis of COAD and provide clues for developing new therapeutic strategies for COAD. Immune infiltration and drug susceptibility results provide important clues for finding new personalized treatment options for COAD. These findings also suggest possible mechanisms that may affect prognosis. These results are the starting point for planning individualized treatment and managing patient outcomes.